1. | Methods Mol Biol. 2011;709:21-37. Source: Institute of Biomedical and Life Sciences, South West London Academic Network, St. George's University of London, London, UK. P.Athanasopoulos@rhul.ac.uk Abstract Duchenne muscular dystrophy (DMD) is a severe muscle wasting X-linked genetic disease caused by dystrophin gene mutations. Gene replacement therapy aims to transfer a functional full-length dystrophin cDNA or a quasi micro/mini-gene into the muscle. A number of AAV vectors carrying microdystrophin genes have been tested in the mdx model of DMD. Further modification/optimization of these microgene vectors may improve the therapeutic potency. In this chapter, we describe a species-specific, codon optimization protocol to improve microdystrophin gene therapy in the mdx model. |
2. | Acta Myol. 2007 Jul;26(1):14-21. Source Department of Pediatrics, Genetic Unit, Faculty of Medicine, Cairo University. Abstract Replicative aging and oxidative stress are two plausible theories explaining the etiology of muscular dystrophy. The first theory indicates that replicative aging of myogenic cells (satellite cells), owing to enhanced myofiber turnover, is a plausible explanation of the progression of Duchenne muscular dystrophy (DMD). The oxidative stress theory indicates that failure of muscle regeneration to keep up with the ongoing apoptosis and necrosis following oxidative stress, that normally associates muscular exercise, leads to muscle atrophy in DMD. To test for these two theories, markers of replicative aging and oxidative stress were assessed in the blood of 30 DMD patients vs. 20 normal healthy age matching controls. Markers of replicative aging showed significantly lower telomerase activity, significantly increased expression of receptors for advanced glycation end products (RAGEs) mRNA and Bax mRNA (an apoptotic gene) in DMD compared to controls. There was a significant increase in markers of oxidative stress among DMD patients compared to controls, measured in terms of increased apoptotic percentage in circulating mononuclear cells, increased lipid peroxidation measured in terms of plasma malondialdehyde (MDA) and increased protein carbonyls. Levels of plasma nitric oxide (NO), which neutralizes oxygen radicals, and expression of inducible nitric oxide synthase (iNOS) mRNA in neutrophils was significantly lower among DMD compared to controls. Biostimulation of WBC by helium neon (He:Ne) laser irradiation induced a significant increase in the expression of iNOS mRNA and plasma NO levels, but still at a lower level compared to controls. He:Ne laser irradiation induced a marked decrease in markers of oxidative stress among DMD patients compared to their level before irradiation, measured in terms of decreased plasma protein carbonyls, decreased plasma MDA, and decreased apoptosis percentage. CONCLUSION: This study points to that oxidative stress is the prime cause for muscle degeneration in DMD and points out to the possible ameliorative effect of He:Ne laser on this PMCID: PMC2949317 Free PMC Article |
PMID: 17915565 [PubMed - indexed for MEDLINE] | |
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3. | Lancet. 2011 Jul 22. [Epub ahead of print] Source Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto 390-8621, Japan. |
PMID: 21784507 [ | |
4. | Skelet Muscle. 2011 Feb 9;1(1):8. Source MRC Functional Genomics Unit, Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, UK. aurelie.goyenvalle@dpag.ox.ac.uk. Abstract ABSTRACT: Antisense oligonucleotides are short nucleic acids designed to bind to specific messenger RNAs in order to modulate splicing patterns or inhibit protein translation. As such, they represent promising therapeutic tools for many disorders and have been actively developed for more than 20 years as a form of molecular medicine. Although significant progress has been made in developing these agents as drugs, they are yet not recognized as effective therapeutics and several hurdles remain to be overcome. Within the last few years, however, the prospect of successful oligonucleotides-based therapies has moved a step closer, in particular for Duchenne muscular dystrophy. Clinical trials have recently been conducted for this myopathy, where exon skipping is being used to achieve therapeutic outcomes. In this review, the recent developments and clinical trials using antisense oligonucleotides for Duchenne muscular dystrophy are discussed, with emphasis on the challenges ahead for this type of therapy, especially with regards to delivery and regulatory issues. |
